In women, as in all mammals, fertility is dependent on the presence in the ovaries of female gametes called “oocytes”. In humans, the oocyte capital is constituted once and for all at birth; the number of oocytes is then comprised between 500 000 and 1 million per ovary. These oocytes are surrounded by a few granulosa cells; this functional group is called an ovarian follicle (Gougeon, A., Endocrine Reviews (1996),17, 121-155). At birth, but also throughout life until menopause, the majority of the ovarian follicles are in a dormant state.
From its constitution, the oocyte capital progressively diminishes: thus, there are approximately 200 000 follicles per ovary at puberty, approximately 80 000 at 20 years of age, approximately 30 000 at 30 years of age, approximately 10 000 at 40 years of age, the capital being practically depleted at around 50 years of age (cf. Gougeon, A. and Lefevre, B., <<Folliculogénèse et maturation ovocytaire>> in Médecine de la reproduction, 3rd edition, Ed. Flammarion, p. 49). The depletion of the oocyte capital corresponds clinically to menopause. The dormant follicles present in the ovary at a given time constitute the “ovarian reserve”.
Two mechanisms are involved in the progressive depletion of the ovarian reserve. Approximately 80% of the follicles disappear at the start of apoptosis, while the remaining 20% start to grow. The latter then begin a long process of development (approximately 6 months) in which a minority of them (approximately 400 over a lifetime) will arrive at the stage of preovulatory follicles containing a mature oocyte which is able to be to be fertilized (Gougeon, A., Endocrine Reviews (1996), 17, 121-155). The majority of the growing follicles disappear through apoptosis leading to their involution; apoptosis strikes them at any stage of their development.
The change from the quiescent follicle stage to the growing follicle stage is a phenomenon which is continuous but of variable intensity. In particular, it accelerates in the 10 to 15 years preceding menopause, from approximately 38 years of age.
The factors stimulating the first stages of growth (starting from the large primary follicle) are relatively well known. They include gonadotropins (LH and FSH) but particularly growth factors and steroids such as androgens. However, the mechanisms controlling the initiation of follicle growth are not well known. It is well established that this stage of folliculogenesis is not dependent on gonadotropins (LH and FSH) (cf. for example Bullun, S. and Adashi, E., Williams Textbook of Endocrinology, Tenth Edition (2003), 587-664). A hormone known as AMH (Anti-Mullerian hormone) could be involved in maintaining the quiescence of the follicles while a peptide known as Kit-Ligand (also called SCF) could be involved in activating the growth of dormant follicles. In addition, a growth factor known as GDF-9 seems to be important for maintaining the growth once it is triggered.
Somatostatin (SST) is a cyclic peptide present in two forms in the organism, one form containing 14 amino acids and one form containing 28 amino acids. The biological activity of these two forms of SST is similar. The SST-14 form is the predominant form in the central nervous system. It inhibits the secretion of the growth hormone by the somatotrope cells of the anterior pituitary. The SST-28 form is preferably expressed in the stomach and the pancreas. The biological activity of SST is induced by means of a series of membrane receptors coupled with a protein G, 5 sub-types of which have been characterized, namely the sub-types SSTR1 to SSTR5 (Reubi, J. C., Cancer Res., 47, 551-558; Resine, T., et al., Endocr. Review, 16, 427-442; Lamberts, SW. et al., Endocr. Review, 12, 450-482).
The presence of SST in the ovary has been demonstrated in several species including pigs (Mori, T. et al., Acta Endocrinol. (Copenh.) (1984), 106(2), 254-259), rats (McNeill, D. L. et al., Am. J Anat. (1987), 179(3), 269-76) and in women (Holst et al., Hum. Reprod. (1994), 9(8), 1448-1451). SST receptors have been identified in the ovary of the rat (Lidor, A. et al., Gynecol. Endocrinol. (1998), 12(2), 97-101) as well as in the human ovary in particular the sub-types 1, 2A and 5 (Strauss et al., Hum. Reprod. (2003), 18, Suppl. 1, P-495).
The contribution of SST in ovarian physiology has been studied by several authors. In rats, the in vivo administration of SST seems to reduce the number of pituitary cells producing LH and FSH as well as the number of preovulatory follicles in the ovary (Nestorovic et al., Histochem. J. (2001), 33(11-12), 695-702). In vitro, SST inhibits aromatase and the production of progesterone, stimulated by FSH, in a model of granulosa cells (Andreani, C. L. et al., Hum. Reprod. (1995), 10(8), 1968-1973). In pigs, SST inhibits the increase in cAMP induced by LH and forskolin in the granulosa cells (Rajkumar, K. et al., J. Endocrinol. (1992), 134(2), 297-306), and seems to inhibit the nuclear maturation of the preovulatory oocyte (Mori, T. et al., Acta Endocrinol. (Copenh.) (1985), 110(3), 408-412). In women, in vitro studies on granulosa cells from preovulatory follicles suggest a direct role of SST in inhibiting the synthesis of IGF-BP1 and of progesterone (Holst, N. et al., Fertil. Steril. (1997), 68(3), 478-482). In women, in vivo, SST is capable of reducing the secretion of LH by the pituitary, reducing the production of androgens and the IGF-1 serum levels. By contrast, SST increases the serum levels of IGF-BP3 (Fulghesu, A. M. et al., Fertil. Steril. (1995), 64(4), 703-708; Piaditis, G. P. et al., Clin. Endocrinol. (Oxf.) (1996), 45(5), 595-604). SST was co-administered with FSH during treatment to induce ovulation in patients who are infertile as a result of a polycystic ovary syndrome. The capacity of SST to reduce the LH serum levels, and to reduce the serum levels of growth hormone and of IGF-I has been confirmed. This endocrine effect is not however accompanied by a significant impact on the follicle growth induced by the administration of FSH (Lidor, A. et al., Gynecol. Endocrinol. (1998), 12(2), 97-101; van der Meer, M. et al., Hum. Reprod. (1998), 13(6), 1465-1469). In summary, until now a marginal effect of SST on the pituitary secretion of LH and on the production of progesterone by the granulosa cells of preovulatory follicles has been reported.